Neuropeptides are neuromodulators that regulate the physiology of cells, synapses, and neural circuits in the brain. For example, opioid neuropeptides are involved in pain and analgesia, and altered opioid neuropeptide levels have been observed in addiction, depression and anxiety, as well as a number of other neurological disorders including Parkinson's disease. Clearly, neuropeptides play a significant role in modulating behavior and cognition, but many aspects of neuropeptide signaling are not well understood. Unlike classical fast synaptic transmitters such as glutamate and GABA, neuropeptides can be released both at the synapse and outside the synapse. Neuropeptides can also diffuse significant distances from where they were released. At distant sites, neuropeptides can continue to function as signals at low concentrations by activating high affinity G-protein coupled receptors. Thus, neuropeptides engage in signaling over much broader spatial and temporal scales than synaptic transmission, and these spatiotemporal characteristics have made it difficult to precisely study how neuropeptide signals propagate throughout the brain. This experimental barrier has left important gaps in our knowledge of how the neural circuits that are responsible for behavior and cognition are modulated. Therefore, in order to overcome this critical barrier and enable neuropeptides to be directly studied in healthy and diseased brain tissue, it is the goal of this proposal is to develop new genetically-encoded optical tools to (1) record and (2) modulate neuropeptide signaling.